19. From embryonic cell to neuron: understanding
the complexity of developmental decisions

Supervisor Pair: Professor Claudio Stern and Dr Karen M Page

“Neural induction”, the process by which early
embryonic cells acquire a neural fate, was classically viewed as a single
response to a molecular signal produced by the “organizer”, the embryonic
inducing tissue. However it now appears that it is a complex cascade of
interlocking decisions, cells passing through successive states. The challenge now
is to dissect the hierarchy and dynamics of the transitions between these
states to build a Gene Regulatory Network (GRN), a model that will not only
enable us to understand this particularly important process in neural
development but also offering a unique opportunity to uncover the full
complexity of the “computer program” driving a developmental decision.

We are using Next Generation
Sequencing and Bioinformatics to identify the transcription factors (TFs)
involved and how they are regulated by signals from the organizer, to define
active enhancers associated with the TFs and to analyse them for binding sites
for other TFs in the set. The student will perform experiments and modelling
work. Experimentally, he/she will undertake in-vivo validation of the
spatiotemporal regulation of the genes and use NanoString analysis to establish
detailed dynamic relationships. This will be the starting point for building a
predictive model of the GRN, including its dynamics. The predictions from this
model will then be tested experimentally both in the embryo and in cultured
embryonic cells and stem cells to validate and test the model in an iterative
way.

This will generate
a predictive model for the transition between early embryonic stem cell and the
neural tube (the early nervous system). The secondary supervisor is studying
how neural tube cells acquire specific identities in response to later signals.
The student will help link these, leading to a comprehensive view of how the
nervous system is built.

Value-added
perspective: This project is not only cross-disciplinary but also highly collaborative. It is linked to a BBSRC
grant in collaboration with Prof Andrea Streit (King’s College London). Dr Page
is experienced in mathematical and computational approaches to modelling
biological systems and is also collaborating with Dr James Briscoe (NIMR, Mill
Hill) to model neurogenesis in the embryonic spinal cord. Complementarity in
this project is therefore particularly strong. Not only does it involve an
experimental lab with expertise in embryology and molecular biology and a group
with mathematical and computational interests at UCL, but it also brings
together 4 teams across 3 institutions (UCL, KCL and NIMR) that are also
partners of the new Crick Institute. We envisage that the student will act as
the connecting bridge between these groups and be involved in driving regular
cross-group meetings to discuss the wider implications of the project.